In pigs, scientists have succeeded in turning cardiac muscle cells into specialized pacemaker cells. Such technology could eventually replace electronic pacemakers, researchers say.

Each year, about 300,000 patients in the U.S. with slow or irregular heart rates receive electronic pacemakers. Pacemakers monitor the heart rate and send an electrical jolt to force contraction when the heartbeat is delayed; they stand in for the heart's natural pacemaker, a cluster of cells in the right atrium (the sinoatrial node) that sends out regular jolts of electricity.

Soon, though, we may not longer need a mechanical implant to make this happen. Scientists are now developing biological pacemakers, created by turning regular heart muscle cells into rhythm-keepers.

Reprogramming the Heart

With the insertion of a human transcription factor gene, researchers have been able to turn cardiomyocytes (cardiac muscle cells) into effective pacemakers in pigs with experimentally induced heart problems. The reprogrammed pacemaker cells kept the heart rate steady during the two-week experiment and upped the heart rate appropriately during physical activity. The study appears today in Science Translational Medicine.

"In essence, we create a new sinoatrial node in a part of the heart that ordinarily spreads the impulse, but does not originate it," says study author Eduardo Marban of Los Angeles' Cedars-Sinai Medical Center. "The newly created node then takes over as the functional pacemaker, bypassing the need for implanted electronics and hardware."

Researchers hope to test these biological pacemakers in humans within three years, study author Eugenio Cingolani said at a press conference yesterday. They plan to apply the technology first to the niche cases where electronic pacemakers fall short.

"If proven to work in [this] disease setting, the technique could eventually become a realistic alternative to regular pacemakers in a broader spectrum of patients," Cingolani says. "Rather than having to undergo implantation of a metallic device that needs to be replaced periodically and can fail or become infected, patients may someday be able to undergo a single-gene injection and be cured of the slow heart rhythm forever."

This work represents a kind of biological engineering called somatic reprogramming, or turning one cell type into another by altering the expression of transcription factors—genes that control the expression of other genes. The landmark example of this technology was reported in 2006, when, by introducing just four genes, researchers transformed fibroblast cells into pluripotent stem cells. That work won the 2012 Nobel Prize in Physiology or Medicine.

"Our work is the first to harness the therapeutic power of somatic reprogramming in a life-threatening disease using a realistic large animal model," Marban said at the conference. "This development heralds a new area of gene therapy where genes are used not only to correct a deficiency disorder, but actually to convert one type of cell into another to treat disease."

A Bridge Device

The researchers gave 12 pigs injections of a non-replicating virus genetically engineered to deliver either the transcription factor TBX-18 or green fluorescent protein as a control into the cells it infects. TBX-18 is a transcription factor that leads to the creation of pacemaker cells in the sinoatrial node during human embryonic development. The pigs had a condition called complete heart block in which the electrical signaling between the top and bottom heart chambers is disrupted, leading to a slowed heart rate. The researchers also gave every pig a back-up electronic pacemaker.

The pigs that received TBX-18 had significantly higher heart rates than the controls throughout the two-week study. They also relied on their back-up pacemakers less than the controls did and were more physically active, with higher maximum heart rates. The pigs receiving TBX-18 also responded significantly better to an injection of an adrenaline-like drug. According to the researchers, that demonstrates that the biological pacemaker can respond to signals from the body's autonomic (involuntary) nervous system.

There are several scenarios in which biological pacemakers could be useful. It could potentially be used to help fetuses with congenital heart block—a condition that often result in stillbirths, Cingolani says. Furthermore, he says, a biological pacemaker could be used when an electronic pacemaker becomes infected and the patient needs a course of antibiotics before a new pacemaker can be installed.

Such antibiotic treatments take six weeks, explains cardiac researcher Nikhil Munshi, of UT Southwestern Medical Center, who was not involved in the work but co-authored a companion article to the new study. Currently, the treatment requires removing the infected device and implanting a temporary pacemaker, which has its own potential for infection. A biological pacemaker, Munshi says, could stand in as a "stopgap" or bridge during the antibiotic regimen.

Munshi and coauthor Eric Olson, also of UT Southwestern Medical Center, note in their companion article that the virus had infected not only the heart, as intended, but also the lung and spleen, and that it will be important to make sure such unintended infections do not cause harm. Munshi and Olson conclude that the study provides "an encouraging indication that a biological pacemaker might eventually be ready for human translation."

Lastly, because this study lasted only two weeks, it remains to be seen whether or not these pacemakers can work for long-term applications, Munshi says.

"We don't know what the long-term durability is," Munshi tells PopMech. "Especially in a situation where a patient has to be treated with antibiotics, if they need an extended period up to six weeks, let's say, I don't think the study answered whether that would be feasible for long-term antibiotic treatments."

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